VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAP/ERK and SAPK/JNK signaling
VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAP/ERK and SAPK/JNK signaling
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DOI：
10.1006/excr.1998.4359
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发表时间：
1999-03-15
影响因子：
3.7
通讯作者：
Hebbel, RP
中科院分区：
文献类型：
--
作者：
Gupta, K;Kshirsagar, S;Hebbel, RP
血管内皮生长因子（VEGF）是一种内皮细胞特异性的有丝分裂原，可促进内皮细胞存活和血管生成。我们最近发现，VEGF可以支持人真皮微血管内皮细胞（HDMEC）和人脐静脉内皮细胞在无血清培养基中的生长。推测VEGF可能是调节凋亡信号转导通路，我们研究了VEGF对饥饿和神经酰胺诱导的HDMEC凋亡的抗凋亡作用的机制。我们观察到VEGF改善了凋亡的时间依赖性增加，如形态学观察、TUNEL测定和DNA片段化所示。另一方面，碱性成纤维细胞生长因子只能部分防止血清饥饿的HDMEC细胞凋亡;血小板衍生生长因子-BB是完全无效的。VEGF以时间和浓度依赖性方式激活细胞外信号调节激酶（ERK）（1）（p44丝裂原活化蛋白激酶; MAPK）和ERK 2（p42 MAPK）的磷酸化。特异性MAPK/ERK抑制剂PD 98059可阻断VEGF诱导的细胞活化及其抗凋亡作用。VEGF的存在也抑制了由血清饥饿和神经酰胺处理引起的应激激活蛋白激酶/c-jun-NH 2-激酶（SAPK/JNK）的持续激活。MAPK通路的激活以及VEGF对SAPK/JNK活性的抑制似乎是决定内皮细胞存活或经历程序性细胞死亡的关键事件。(C)北京：科学出版社.
Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, promotes endothelial cell survival and angiogenesis. We recently showed that VEGF can support the growth of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells in serum-free medium. Reasoning that VEGF might be modulating apoptotic signal transduction pathways, we examined mechanisms involved in the anti-apoptotic effect of VEGF on starvation- and ceramide-induced apoptosis in HDMEC. We observed that VEGF ameliorated the time-dependent increase in apoptosis, as demonstrated by morphologic observations, TUNEL assay, and DNA fragmentation. On the other hand, basic fibroblast growth factor only partially prevented apoptosis in serum-starved HDMEC; platelet-derived growth factor-BB was completely ineffective. VEGF activated the phosphorylation of extracellular signal regulated kinase (ERK)(1) (p44 mitogen-activated protein kinase; MAPK) and ERK2 (p42 MAPK) in a time- and concentration-dependent manner. Both the VEGF-induced activation and its anti-apoptotic effect were prevented by the specific MAPK/ERK inhibitor PD98059. The presence of VEGF also inhibited the sustained activation of stress-activated protein kinase/c-jun-NH2-kinase (SAPK/JNK) caused by serum starvation and ceramide treatment. Activation of the MAPK pathway together with inhibition of SAPK/JNK activity by VEGF appears to be a key event in determining whether an endothelial cell survives or undergoes programmed cell death. (C) 1999 Academic Press.